Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer

Final analysis from INT-0137 (S9313)

Hannah M. Linden, Charles M. Haskell, Stephanie J. Green, C. Kent Osborne, George W. Sledge, Charles L. Shapiro, James N. Ingle, Danika Lew, Laura F. Hutchins, Robert B Livingston, Silvana Martino

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Purpose: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

Original languageEnglish (US)
Pages (from-to)656-661
Number of pages6
JournalJournal of Clinical Oncology
Volume25
Issue number6
DOIs
StatePublished - Feb 20 2007
Externally publishedYes

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Anthracyclines
Cyclophosphamide
Doxorubicin
Breast Neoplasms
Disease-Free Survival
Survival
Granulocyte Colony-Stimulating Factor
Tamoxifen
Estrogen Receptors
Appointments and Schedules
Anti-Bacterial Agents
Drug Therapy
iodonitrotetrazolium
Pharmaceutical Preparations
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer : Final analysis from INT-0137 (S9313). / Linden, Hannah M.; Haskell, Charles M.; Green, Stephanie J.; Osborne, C. Kent; Sledge, George W.; Shapiro, Charles L.; Ingle, James N.; Lew, Danika; Hutchins, Laura F.; Livingston, Robert B; Martino, Silvana.

In: Journal of Clinical Oncology, Vol. 25, No. 6, 20.02.2007, p. 656-661.

Research output: Contribution to journalArticle

Linden, HM, Haskell, CM, Green, SJ, Osborne, CK, Sledge, GW, Shapiro, CL, Ingle, JN, Lew, D, Hutchins, LF, Livingston, RB & Martino, S 2007, 'Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: Final analysis from INT-0137 (S9313)', Journal of Clinical Oncology, vol. 25, no. 6, pp. 656-661. https://doi.org/10.1200/JCO.2006.07.0847
Linden, Hannah M. ; Haskell, Charles M. ; Green, Stephanie J. ; Osborne, C. Kent ; Sledge, George W. ; Shapiro, Charles L. ; Ingle, James N. ; Lew, Danika ; Hutchins, Laura F. ; Livingston, Robert B ; Martino, Silvana. / Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer : Final analysis from INT-0137 (S9313). In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 6. pp. 656-661.
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abstract = "Purpose: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48{\%} of eligible patients were node-negative and 48{\%} were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95{\%} CI) were 88{\%} (87{\%} to 90{\%}) on AC and 89{\%} (87{\%} to 91{\%}) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.",
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T1 - Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer

T2 - Final analysis from INT-0137 (S9313)

AU - Linden, Hannah M.

AU - Haskell, Charles M.

AU - Green, Stephanie J.

AU - Osborne, C. Kent

AU - Sledge, George W.

AU - Shapiro, Charles L.

AU - Ingle, James N.

AU - Lew, Danika

AU - Hutchins, Laura F.

AU - Livingston, Robert B

AU - Martino, Silvana

PY - 2007/2/20

Y1 - 2007/2/20

N2 - Purpose: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

AB - Purpose: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

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